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Application of a Bolm ligand analog in catalysis
Malatinec, Štefan ; Kotora, Martin (advisor) ; Matoušová, Eliška (referee)
Bolm`s ligand belongs to the group of 2,2'-bipyridines, which represents a class of C2 symmetric ligands. These ligands form complexes with Lewis acids, which could be used in asymmetric catalysis, for example in the ring-opening of epoxides. Bolm`s ligand analogue was prepared and the enantioselectivity of the ring-opening reaction of cis-stilben oxide with aniline and variety of substituted benzyl alcohols catalyzed by scandium(III) triflate was studied as a part of this bachelor thesis. The enantioselectivity of the reaction using Bolm's ligand analogue was compared to that of Bolm`s ligand. Key words: synthesis, catalysis, bipyridines
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Synthesis of five-membered ring analogues of Amaryllidaceae alkaloids
Kvapilová, Pavlína ; Matoušová, Eliška (advisor) ; Jindřich, Jindřich (referee)
This bachelor Thesis deals with the synthesis of polycyclic compounds containing all-carbon quaternary centres. Quaternary centres with a similar substitution as our target compounds can be found in some natural products. In particular, nitrogen-containing compounds, structurally related to Amaryllidaceae alkaloids, have been prepared in this work. For the construction of the all-carbon quaternary centre we used tandem cyclization/Suzuki cross-coupling and halocarbocyclisation reaction sequence. The first part of the Thesis is dedicated to compounds that have a nitrogen atom protected by a p-methoxybenzenesulfonyl group. In the second part we deal with the preparation of N-methyl derivatives of these compounds. The third part is dedicated to the synthesis of a protected amine from 2-oxazolidinone, which we have unsuccessfully used for the preparation of polycyclic compounds with a hydroxyethyl group on the nitrogen atom. Key words: Synthesis, Amaryllidaceae alkaloids, polycyclic compounds, biological activity
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Synthesis and characterization of new insulin analogs with a triazole bridge at the C-terminus of the B chain
Kuntová, Vendula ; Jiráček, Jiří (advisor) ; Ryšlavá, Helena (referee)
Insulin is a peptide hormone responsible for maintaining glucose homeostasis in the circulation. Insulin interacts with two isoforms of the insulin receptor, IR-A and IR-B, which have different tissue distribution. IR-A is supposed to have rather mitogenic function and IR-B rather metabolic function. The goal of this study was to develop insulin analog, which will be more selective for IR-B than human insulin. We prepared three new insulin analogs with a 1,2,3-triazole bridge at the positions B26 and B29. The triazole bridge was formed by Cu(I)- catalysed cycloaddition between side chains of azidopentanoic acid (N3Pent) at B26 and propargylglycine (Prg) at B29. The analogs differed in configurations on C carbons of unusual amino acids at the positions B26 and B29. Specifically, we prepared insulin analog 1 with D- N3PentB26 and D-PrgB29, insulin analog 2 with D-N3PentB26 and L-PrgB29 and insulin analog 3 with L-N3PentB26 and D-PrgB29. New analogs were tested for their binding to both isoforms (IR-A and IR-B) of the insulin receptor. Analogs 1 and 2 were less potent in binding than human insulin and had no selectivity for receptor isoforms. Analog 3 was 4-times more potent in binding to IR-B and 2-times more potent in binding to IR-A than human insulin. However, the binding selectivity of the...
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Analogues of IGF-1 for the study of interactions of the hormone with the receptors for IGF-1 and insulin
Macháčková, Kateřina ; Jiráček, Jiří (advisor) ; Obšilová, Veronika (referee) ; Šulc, Miroslav (referee)
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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Carborane structural blocks in medicinal chemistry
Nekvinda, Jan ; Grüner, Bohumír (advisor) ; Machara, Aleš (referee) ; Janoušek, Zbyněk (referee)
This work deals with carborane and metallacarborane clusters, in terms of their fundamental chemistry and complexation with cyclodextrins, and in the context of emerging pharmacophores applicable in medicinal chemistry. Arguably, the most important part of this work is the preparation of cobalt bis(dicarbollide) sulfamide derivatives. The sulfamido group is attached to the metallacarborane carbon vertex by an alkyl chain that may be modified in its length. This was accomplished by, firstly, the abstraction of the acidic hydrogen, located on the {CH}-vertex from the metallacarborane, by reaction with lithium base, followed by, secondly, reaction with electrophilic agents (PFA, oxirane and oxetane), which leads to a cascade of reactions to give the desired sulfamide derivatives. These compounds were then tested by collaborators in other institutes for in vitro and in vivo activity towards Carbonic Anhydrase IX (CA IX), which is an enzyme associated with tumour growth. In vivo tests on mice have shown that these types of substances are able to effectively reduce tumour size by 30%. The synthetic research continued with the preparation of sulfonamide compounds of the isomers of the carborane series. The reactions began exclusively with propylhydroxy carborane starting materials, which provide optimum...
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Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...
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Synthesis of peptidic inhibitors targeting PA-PB1 interface of influenza RNA polymerase
Palacková, Miroslava ; Machara, Aleš (advisor) ; Veselý, Jan (referee)
The submitted Thesis deals with preparation of a hexapeptides inhibiting protein-protein interaction of PA-PB1 subunits of influenza RNA polymerase. Crucial part of the Thesis represent modifications of particular small hexapeptide at its two "hot spots". It means at positions that significantly contribute to the binding of both subunits. These modifications resulted in preparation of two series of distinct hexapeptides. With regards to the fact that one designed hexapeptide contains unnatural and commercially unavailable amino acids this amino acid had to be prepared from simple building blocks. Apart from aforementioned work the Thesis also covers effort to prepared bicyclic peptide that contains sequences of peptidic inhibitor of protein-protein interactions and also cell-penetration peptide. Key words: synthesis, peptides, inhibitors, influenza, polymerase
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The Role of Human Figure in Indicative Test of School maturity
Michálková, Anna ; Klusák, Miroslav (advisor) ; Presslerová, Pavla (referee)
The thesis deals with the role of drawing of a human figure in Jirásek's Orientation Test of school maturity. The aim is to contribute to the development of theory of tested abilities. Empirical material consists of the works of preschool children in the Oriental Test of School Maturity, including the one for verbal thinking and in a selected set of Raven color progressive matrices. Data collection took place in two phases, four months apart. The underlying question is whether performance in drawing of a human figure will correlate more closely with performance in other tasks that are also oriented towards nonverbal (vs. verbal) and infralogical (vs. logical) operations. It turned out that it is not the case since the correlation is related rather to the degree of the general intellectual level. When analyzing developmental correlations within the given time frame, the development of drawing of a male character was grasped as a variable working synchronously with the development of other tasks. It was also grasped in the first phase as an independent variable and also as a dependent variable. Applying stricter correlation rates it has been shown that in a time interval of 4 months, the initial level of drawing of a human figure does not significantly affect development in other areas.Weaker...
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